We have demonstrated that combined short-term treatment with either a co-stimulation orientated approach, albeit based upon use of a clinically unacceptable thrombogenic anti-CD154 mAb, or a triple therapy/ power mix regimen protect cynomolgus islet allografts from rejection during active treatment. In fact, graft survival endured after drug withdrawal, sometimes for over 7 months. With both regimens, slowly progressive loss of graft function and the absence of robust anti-donor antibody response or clear pathologic signs of rejection in recipients of grafts are noted in recipients whose grafts fail after lengthy periods of drug-free survival. These data suggest but by no means prove that processes other than rejection contribute to or cause graft failure. We hypothesize that massive, clinically unacceptable loss of islets due to inflammation and thrombosis in the peri- transplant period and inability to produce tolerance/ indefinite islet allograft survival are inextricably intertwined processes. Antigen presented in an inflamed milieu provokes aggressive and tolerance-resistant immunity. Two strategies that have produced drug-free, albeit not indefinite, cynomolgus islet allograft survival serve as a platform for innovation. Believing we are on the cusp of producing durable drug-free islet allograft survival and tolerance, we aim to optimize our two therapeutic strategies. In an effort to develop tolerizing therapies amenable to clinical application, we place heavy emphasis on efforts to i) blunt the inflammation- and thrombosis- associated loss of islets, thereby enabling use of resilient islets that evoke less menacing, less tolerant-resistant immune responses ii); magnify commitment to the regulatory T cells (Tregs) phenotype and stabilize their viability and function and iii) utilize biologic agents in both regimens better suited for clnical application. PUBLIC HEALTH RELEVANCE: Many islets gathered for transplantation perish from biologic insults suffered from the time of islet harvest through purification, culture and post transplantation until the islets develop a new blood supply from donor blood vessels, a situation that has imperiled clinical deployment of islet transplantation because multiple donors are required to render a single recipient even temporarily diabetes free. We hypothesize that massive, clinically unacceptable loss of islets due to inflammation and thrombosis in the peri-transplant period and inability to produce tolerance/ indefinite drug free islet transplant surviva are inextricably intertwined processes. Two strategies that have produced drug-free, albeit not indefinite, non-human primate islet survival of genetically mismatched islets now serve as a platform for innovation. Believing we are on the cusp of being able to produce durable drug-free islet transplant survival and tolerance, we aim to optimize our two therapeutic strategies. In an effort to develop tolerizing therapies amenable to clinical application, we place heavy emphasis on efforts to i) blunt the inflammation- and thrombosis- associated loss of islets, thereby enabling use of resilient islets that evoke less menacing immune responses ii); magnify the generation and durability of protective-, not destructive-type immune cells and iii) utilize biologc agents suitable for clinical application.